Resting State and Functional Connectivity: Previous studies have shown diverse effects of alcoholism on resting state MRI (rsMRI) connectivity. Long-term alcoholics who were currently in a period of sobriety showed decreased synchrony of limbic reward regions. The results demonstrated abnormal functional connectivity both within and between-network in AD, further supporting the concept that AD is a disorder affecting neural networks. The impaired connectivity in the resting state networks was associated with increased impulsivity in AD. Our findings suggest that the altered resting-state functional connectivity patterns can differentiate AD subjects from HC, and may become an important biomarker for alcohol dependence severity and treatment efficacy (Zhu et al., manuscript prepared for submission). fMRI analysis method development: We developed a linear time-invariant model based on statistical time series analysis in the Fourier domain for single subjects and applied this method to functional MRI (fMRI) blood-oxygen level-dependent (BOLD) multivariate data. This is especially important for experimental designs involving multiple states (either stimulus or drug induced) that may alter the form of the response function (Rio et al., Comput Math Methods Med. 2013; 2013) Medication Studies: a) Naltrexone Our section has designed fMRI tasks and analyzed the imaging data of Effect of Naltrexone on Craving and Ethanol-Induced Brain Activity, by the CATE (Dr. George) section. Positively reinforcing properties of alcohol is in part mediated by activation of the ventral striatum (VS). Alcohol-induced release of endogenous opioids is thought to contribute to this response. Preclinical studies show that the opioid antagonist naltrexone (NTX) can block this cascade, but its ability to do so in treatment seeking alcoholics has not been examined. Participants received a saline infusion followed by alcohol, and also viewed affective stimuli in an MR scanner. Irrespective of medication treatment condition, and in contrast to prior findings in social drinkers, alcohol infusion did not activate the VS in the alcohol dependent patients. Unexpectedly, and across all other conditions, VS activation was greater in NTX treated patients than in the PLC group. NTX treated patients also reported increased craving in response to alcohol cue exposure compared to PLC subjects (Spagnolo et al., accepted publication, ACER 2014). b) PTSD: Our section has designed fMRI imaging tasks and analyzed the imaging data of The Effect of NK1R Antagonism on Alcohol Craving and PTSD Symptoms in Alcohol Dependent Patients with PTSD, by the CATE (Dr. George) Section. Post-traumatic stress disorder (PTSD) and alcoholism are frequently co-morbid. This study was designed to determine the neural effects of neurokinin 1 (NK1) antagonist aprepitant on alcohol-dependent subjects with PTSD. Fifty-three patients with PTSD and alcoholism were admitted for 4 weeks to this experimental medicine study. In this randomized and double-blind study subjects fMRI responses to stimuli with positive or negative emotional valence were analyzed. In this study we found treatment group robustly potentiated ventromedial prefrontal cortex (vmPFC) responses to aversive visual stimuli. This region of brain is critical for extinction of fear memories and in alcohol craving and relapse risk, our finding suggests that NK1 antagonism, rather than acutely attenuating stress responses, might be a useful pharmacological treatment to enhance the effect of extinction-based cue-exposure therapies (Kwako, et al., accepted publication AJP 2014). c) Varenicline: Our section has designed fMRI imaging tasks and analyzed the imaging data of the study conducted by Section on Human Psychopharmacology (Dr. Ramchandani). In this double-blind randomized study subjects were randomized to receive Varenicline or placebo for 3 weeks. Participants underwent an fMRI scan while performing a variation of the MID task designed to evaluate the incentive salience of alcohol cues. A direct contrast of treatment groups showed significantly lower activation in Varenicline compared to placebo group. These results indicate significant activation of striatal regions to alcohol cues and notification of alcohol reward in the placebo but not in the Varenicline group. This suggests that Varenicline may exert its effects by modulating the neural substrates underlying motivation for and incentive salience of alcohol reward in heavy drinkers (Vatsalya, et al., submitted JAMA Psychiatry). d) BMS: Our section has designed fMRI imaging tasks and analyzed the imaging data of the study designed and conducted by the Section on Clinical and Treatment Evaluation. Patients went under a randomized double-blind pexacerfont. After reaching steady state, subjects were assessed for fMRI responses to alcohol-related stimuli or stimuli with positive or negative emotional valence. Based on conventional analyses of fMRI data, Pexacerfont treatment had no effect (Manuscript submitted, NPP). e) Pioglitozone: Our section is providing design, implementation and analyses of fMRI component of a study aimed to evaluate the role of proinflammatory signalling in alcohol craving. The peroxisome proliferator-activated receptor &#947; (PPAR&#947;) agonist pioglitazone, which modulates glial activity, will be used as an experimental treatment. Guided imagery auditory scripts will be used as an established set of stimuli to induce craving. Low dose lipopolysaccharide (LPS) administration which activates proinflammatory signaling will be used as a novel challenge, and evaluated for its ability to provoke alcohol craving. If LPS in fact induces alcohol craving, the present design will allow evaluation of whether pioglitazone can inhibit this response. f) GSK: Our section is providing design, implementation and analyses of fMRI component of a study aimed to evaluate pexacerfont, an orally available, brain penetrant selective CRH1 antagonist for its ability to modulate emotional and motivational processes in anxious, recently detoxified alcohol dependent pa Other Collaborations In addition to LCTS, Our section has provided fMRI expertise to other sections and laboratories within NIAAA Intramural program. Among those: We provided fMRI support material to The Section on Clinical Psychoneuro-endocrinology and Neuropsychopharmacology ((CPN) Dr. Lorenzo Legio). Through data analysis from our Monetary Incentive Delay (MID) studies we provided support to a study on the potential of glucagon-like peptide-1 receptor as a treatment target in alcohol use disorder: evidence from human genetic association studies and a mouse model of alcohol dependence (submitted for publication AJP). Our section has designed and assisted the CPN section in conducting a study involving Ghrelin, a 28-amino acid peptide acting as the endogenous ligand for the growth hormone secretagogue receptor (GHS-R). Ghrelin stimulates appetite by acting on the hypothalamic arcuate nucleus (ARC), a region that controls the intake of food and other substances, including alcohol. The imaging component of this study involves investigating how the infusion of Ghrelin and acute ethanol impacts tasks performance and resting state fMRI. Our section has also provided support in designing the fMRI component of a B2B study (Dr. Mary Lee) by CPN section to study the effects of oxytocin in alcohol dependence. Our Section has also assisted the Section on Nutritional Neurosciences (Dr. Joseph Hibblen), Laboratory of Membrane Biochemistry and Biophysics to design, implement, and conduct the Neuroimaging Omega-3 and Reward in Adults with ADHD trial.